Epigenetic dysregulation is near universal in cancer, driving progression, plasticity, and therapy resistance. Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy and one third of patients develop treatment refractory disease. Around 22% of germinal centre B-cell DLBCL and around 25% of follicular lymphoma harbour activating mutations in the epigenetic regulator EZH2. EZH2 inhibitors are in clinical trials for EZH2-mutant DLBCL and FDA-approved for relapsed/refractory EZH2-mutant follicular lymphoma. However, EZH2 inhibitor monotherapy has shown limited efficacy in patients, particularly in DLBCL, highlighting the need for new therapeutic approaches.
Our lab has discovered that dependency on EZH2 predicts co-dependency on another epigenetic regulator, Menin, across multiple tumour types. Menin inhibitors are showing great promise in clinical trials in acute leukemia, providing an opportunity to repurpose them to treat EZH2-dependent malignancies such as DLBCL. We show that Menin inhibition drives specific lymphoma cell growth inhibition, G1 cell cycle arrest, and enhanced immunogenicity, indicating potential as a monotherapy or combination with immunotherapy. To understand mechanisms of Menin and EZH2 inhibitor response and resistance, we performed a whole genome CRISPR screen in an EZH2-mutant DLBCL cell line. Our screen revealed common and distinct pathways driving resistance to EZH2 and Menin inhibition. In particular, disruption of cell cycle regulators frequently mutated in DLBCL is a common mechanism of resistance to both inhibitors. However, combining Menin and EZH2 inhibition dramatically enhances growth inhibition and bypasses resistance mediated by cell cycle dysregulation. In addition, our screens have revealed novel therapeutic targets to overcome EZH2 inhibitor resistance in EZH2-mutant DLBCL.